Controlled release dosage forms are increasingly important for delivering drugs to an animal for obtaining good therapy. The controlled release of drug by a dosage form indicates control is exercised over both the duration and the profile of a drug release program. Controlled release dosage forms provide many therapeutic advantages over conventional dosage forms. For example, one major and important advantage is the lessening of fluctuation in blood plasma drug concentrations. The pharmacologic basis for minimizing fluctuations in plasma level derives from three therapeutic principles. First, every drug has a therapeutic blood level that must be reached if the desired therapeutic benefit is to be achieved from the administered drug. Second, most drugs have blood plasma levels that define the limits above which side effects may appear, and this can be substantially avoided by the use of controlled release dosage forms. Third, the drug plasma concentration response for most drugs is proportional to the concentration administered, which dictates of the need for controlled release dosage forms. These pharmacologic principles indicate a need for keeping plasma concentrations within a therapeutic level, and accordingly, addresses the need for a controlled release dosage form to achieve the intended results.
The dosage form used for drug administration can influence the course of therapeutic activity by affecting the profile of drug concentration in the blood. For example, the blood level profile of a drug following administration by a prior art conventional dosage form is defined by an initial high peak, followed by a rapid decline, in both the slope and the duration of the drug. The initial high peak typically substantially exceeds the therapeutic plasma concentration range and the level fluctuates in peaks and troughs above and below the desired therapeutic level. In contrast, controlled release dosage forms can minimize the fluctuations known to the prior art, minimize or even avoid the peaks in blood level concentration and the following valley in blood level concentrations. A controlled dosage form can extend also the duration of therapeutic index levels over time.
In view of the above presentation it is immediately evident a pressing need exists for a controlled release dosage form for administering a therapeutically-important drug, such as a calcium channel blocking drug to a patient in need of calcium channel blocking therapy. The expression "calcium channel blocking drugs" also are known as calcium channel blockers, calcium channel antagonist, or calcium antagonists. The calcium channel blockers possess broad pharmacological use and they exhibit pronounced properties such as long-lasting vasodilating effects accompanied by an energy-sparing effect on cardiac metabolism, antiarrhythmic and antianginal action on cardiac muscle, vascular spasmolytic action, antihypertensive action, spasmolytic action on smooth muscle of the gastrointestinal and urogenital tracts and the cerebrovascular and respiratory system, useful for antihypercholesterolemic action, protection of the ischemic myocardium, inhibition of irritable bowel syndrome and esophagal spasm, inhibition of migraine, inhibit vascular calcium contraction, reduce cardiac contractile force, inhibit calcium mediated tracheal contraction, inhibit calcium uptake in primary cells, myocardial ischemia and hypertension. The calcium antagonist drugs that possess these therapeutic properties and can be administered by the dosage form and the method of the invention comprise a member selected from the group consisting of verapamil, nifedipine, diltiazem, bepridil, nicardipine, nitredipine, isradipine, niludepine, nisoldipine, felodipine, cinnarizine, flunarizine, perhexiline, amlodipine, or as their pharmaceutically acceptable salts or as their pharmaceutically acceptable derivatives. The pharmaceutically acceptable salts are acid addition salts of non-toxic pharmaceutically acceptable acids. The acids include inorganic acids and organic acids, and consequently, the salt can be an inorganic or organic salt. The pharmaceutically acceptable salts for the purpose of this invention consist of a member selected from the group consisting of inorganic, hydrochloric, hydrobromic, hydriodic, phosphoric, sulfuric, nitric, and the like, organic, trifluoroacetic, trichloroacetic, acetic, glycolic, pamoic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, mandelic, benzoic, cinnamic, methane sulfonic, ethane sulfonic, salicylic, p-toluenesulfonic or cyclohexanesulfamic. The pharmaceutically acceptable derivatives include alkyl substituted and ester derivatives. The drugs are known to the medical art in USAN and the USP Dictionary of Drug Names, 1961-1990 Cumulative List, published 1990 by United States Pharmacopeial Convention, Inc.; and in Physician's Desk Reference, 45 Ed. 1991, published by Medical Economy Company, Inc.